HIV-1 reverse transcriptase (RT) is a critical target for the antiviral treatment of AIDS. Thus, detailed knowledge of the structure and function of RT has important clinical and biological consequences. The proposed work will entail the use X-ray crystallography to determine structures of wild-type and drug-resistant HIV-1 RT in the presence and absence of nucleic acid substrates and inhibitors. The laboratories of Dr. Edward Arnold at the Center for Advanced Biotechnology and Medicine and Rutgers University and Dr. Stephen H. Hughes at the NIH Cancer Research and Development Center have obtained structures of HIV-1 RT with and without bound nucleic acid substrates and inhibitors. HIV-1 RT complexes containing DNA/DNA, RNA/DNA, and RNA/RNA template-primers and bound dNTP and nucleoside analog inhibitors will be studied. All of the structures should be obtainable using crystal forms that have previously yielded structures. The new structural information from these studies will enhance our understanding of mechanisms of polymerase and RNase H catalysis, of drug resistance, and of polymerase fidelity. In addition to having fundamental scientific value, these results will have utility for the development of improved treatments for HIV infection.